This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lyme neuroborreliosis is caused by the spirochete B. burgdorferi, and is often manifest by neurocognitive deficits. As a possible mechanism for Lyme neuroborreliosis we hypothesized that B. burgdorferi induces in the central nervous system the production of inflammatory mediators, with concomitant neuronal and/or glial apoptosis. To test our hypothesis we set up an ex vivo model consisting of freshly collected slices from brain cortex of l rhesus macaques, and allowed live B. burgdorferi to penetrate the tissue. Numerous transcripts of genes that regulate inflammation as well as both oligodendrocyte and neuronal apoptosis were significantly perturbed, as assessed by DNA microarray analysis. Transcriptional fold-increases of 7.43 (p = 0.005) for the cytokine TNF-alpha and 2.31 (p = 0.016) for the chemokine IL-8 were also detected by real-time-PCR array analysis. The immune mediators IL-6, IL-8, IL-1beta, COX-2, and CXCL13 were visualized in glial cells in situ by immunofluorescence staining and confocal microscopy. Concomitantly, significant proportions of both oligodendrocytes and neurons undergoing apoptosis were present in spirochete-stimulated tissues. IL-6 production by astrocytes, and oligodendrocyte apoptosis were also detected, albeit at lower levels, in rhesus macaques that had received in vivo intraparenchymal stereotaxic inoculations of live B. burgdorferi. These results provide proof of concept for our hypothesis. A manuscript including these results was published in the American Journal of Pathology.